title: Suppression of cAMP by phosphoinositol/Ca2+ pathway in the cardiac kappa-opioid receptor.
abstract: To determine whether the phosphoinositol/Ca2+ pathway interacts with the adenylate cyclase/adenosine 3',5'-cyclic monophosphate (cAMP) pathway in the cardiac kappa-receptor, the effects of U-50488, a specific kappa-receptor agonist, on the intracellular Ca2+ concentration ([Ca2+]i) and forskolin-induced accumulation of cAMP in rat ventricular myocytes were determined after interference of the phosphoinositol/Ca2+ pathway. U-50488 suppressed the forskolin-induced accumulation of cAMP and elevated [Ca2+]i, which were blocked by norbinaltorphimine, a specific kappa-receptor antagonist, and pertussis toxin. The effects of U-50488 were qualitatively similar to those of A-23187, a Ca2+ ionophore, but opposite to those of 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (BAPTA)-acetoxymethyl ester (AM), a [Ca2+]i chelator. Abolition of U-50488-induced elevation of [Ca2+]i by BAPTA-AM also abolished the effect of U-50488 on forskolin-induced accumulation of cAMP. Inhibition of the phospholipase C by specific inhibitors, U-73122 and neomycin, abolished the effects of U-50488 on both [Ca2+]i and forskolin-induced accumulation of cAMP. The results showed for the first time that kappa-receptor stimulation may suppress cAMP accumulation via activation of the phosphoinositol/Ca2+ pathway in the rat heart.
authors.affiliation: Department of Physiology, Faculty of Medicine, University of Hong Kong, Hong Kong.
authors.forename: W M
authors.initials: WM
authors.lastname: Zhang
authors.forename: T M
authors.initials: TM
authors.lastname: Wong
mesh_terms: D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer / Q000494:pharmacology; D037361:Adenylate Cyclase Toxin; D000818:Animals; D000001:Calcimycin / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D002478:Cells, Cultured; D002614:Chelating Agents / Q000494:pharmacology; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism*; D004533:Egtazic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D006321:Heart / Q000187:drug effects; D006352:Heart Ventricles; D007700:Kinetics; D008297:Male; D009206:Myocardium / Q000166:cytology / Q000378:metabolism*; D009271:Naltrexone / Q000031:analogs & derivatives* / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology*; D037342:Pertussis Toxin; D010716:Phosphatidylinositols / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017473:Receptors, Opioid, kappa / Q000037:antagonists & inhibitors / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects; D010566:Virulence Factors, Bordetella / Q000494:pharmacology
chemical_list: D037361:Adenylate Cyclase Toxin; D002614:Chelating Agents; D009292:Narcotic Antagonists; D010716:Phosphatidylinositols; D017473:Receptors, Opioid, kappa; D010566:Virulence Factors, Bordetella; C070379:1,2-bis(2-aminophenoxy)ethane N,N,N',N'-tetraacetic acid acetoxymethyl ester; D005576:Colforsin; C051844:norbinaltorphimine; D000001:Calcimycin; D004533:Egtazic Acid; D009271:Naltrexone; D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; D000242:Cyclic AMP; D037342:Pertussis Toxin; D002118:Calcium